Abstract In this Small Business Innovation Research (SBIR) Phase I project, Functional Fluidics proposes to develop a novel anti-sickling/anti-adhesive therapy and its companion diagnostic in sickle cell disease (SCD). SCD- related complications, such as heart attack and stroke, cause considerable mortality and morbidity worldwide. Vaso-occlusive crisis (VOC), the hallmark of SCD, is a recurrent painful episode that primarily drives patients to seek medical cares. Despite the advances in pain management, a class of novel therapeutic agents that specific target on the underlying molecular mechanisms have shown a greater promise to effectively reduce the frequency, severity and duration of these acute crises, and hopefully become the First-in-Class drugs for treating SCD. At the same time, the growing efforts in drug development also require the corresponding companion diagnostic test to better administrate a new therapy in individual patient with SCD. Unfortunately, these are no standardized clinical tools to monitor the status and disease and assess therapeutic outcomes. Functionally, our new hemoglobin modifiers (PP compounds) work in a multi-action model for 1. prevention of hypoxia-induced polymerization of hemoglobin S; 2. increase of hemoglobin affinity to oxygen, and 3. inhibition of the interaction between intra-cellular hemoglobin and cell membranes. These effects are anticipated to not only lower the rate of VOC, but also ameliorate the overall SCD complications. On the other hand, the proposed blood function assay utilizes microfluidic technologies to simulate in vivo microcirculation and evaluate pathological cell adhesion under physiological flow conditions. As a result, the testing is believed to be clinically relevant. We propose to use this microfluidic cell adhesion assay to evaluate therapeutic outcomes of hemoglobin modifiers on animal model to promote the understanding these investigational compounds for the future development in clinical trials. We envision that our proposed work will eventually lead to the first personalized treatment to reduce the complications of SCD.